Bidirectional transport of iminodiacetic organic anion analogues between plasma and hepatocyte

The kinetics of organic anions are well described and back-diffusion from hepatocyte to plasma is accepted. Although iminodiacetic (IDA) analogues, as organic anions, should also show bidirectional transport between hepatocyte and plasma, this has not been directly demonstrated heretofore. The aim of this study was to directly demonstrate back-diffusion and to quantify it in terms of its fractional rate constant. Kinetics of diethyl IDA were studied in three anaesthetised dogs in which femoral arterial and hepatic venous samples were obtained after injection of tracer into (a) a peripheral vein or (b) hepatic artery or portal vein. Arterial time-concentration curves were also compared between peripheral venous and either hepatic arterial or portal venous injections. Time-activity curves were recorded from regions of interest over the cardiac blood pool and peripheral hepatic parenchyma in 30 patients undergoing routine IDA hepatobiliary imaging with diethyl IDA or mebrofenin and fractional rate constants of clearance of IDA from the hepatocyte compared between compartmental and deconvolution analyses. After peripheral injection in dogs, there was an early arteriovenous concentration gradient across the liver indicating an hepatocyte extraction fraction in the three animals of 0.9, 0.8 and 0.6. The net extraction fraction decreased exponentially over 40 min. Time-concentration curves from hepatic vein and femoral artery were virtually superimposed following intrahepatic injections. Peripheral arterial curves, however, had different shapes according to whether injections were intrahepatic or peripheral, and were consistent with significant back-diffusion. In clinical studies, the blood disappearance curves were fitted as the sum of two exponentials and the liver curves as the difference of two exponentials (with rate constants denoted alpha1h and alpha2h). Based on compartmental analysis of the blood curves, the sum of the fractional rate constants of tracer movement from hepatocyte to bile canaliculus (k32) and to plasma (k12) was similar to and correlated with the rate constant, alpha, of the hepatocyte impulse response function (r=0.62, n=30, P<0.001). In contrast, alpha1h and alpha2h were respectively clearly greater and smaller than alpha. Moreover, neither of these hepatic rate constants correlated with alpha. Diffusion of IDA from hepatocyte to blood is significant and even in the presence of normal liver function accounts for about 50% of IDA transport out of the hepatocyte. It should be taken into account in pharmacokinetic studies based on either compartmental or deconvolution analysis.